CTLA4
Cytotoxic T-lymphocyte-associated protein 4 is a receptor on T Helper cells that functions as an immune checkpoint and downregulator of immune responses. Mutations in CTLA-4 are associated with insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, systemic lupus erythematosus (SLE), celiac disease, primary biliary cirrhosis, thyroid-associated orbitopathy, multiple sclerosis, and other autoimmune diseases. The spliced variant of CTLA-4 in SLE is present in the patient's serum. Haploinsufficiency of CTLA-4 causes the immune system disorder known as CTLA-4 deficiency or CHAI disease.
Full Name
Cytotoxic T-Lymphocyte Associated Protein 4
Function
Inhibitory receptor acting as a major negative regulator of T-cell responses. The affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of their cognate stimulatory coreceptor CD28.
Biological Process
Adaptive immune response Source: UniProtKB-KW
B cell receptor signaling pathway Source: UniProtKB
Cellular response to DNA damage stimulus Source: UniProtKB
Immune response Source: ProtInc
Negative regulation of B cell proliferation Source: UniProtKB
Negative regulation of immune response Source: Ensembl
Negative regulation of regulatory T cell differentiation Source: BHF-UCL
Negative regulation of T cell proliferation Source: Ensembl
Positive regulation of apoptotic process Source: UniProtKB
Regulation of regulatory T cell differentiation Source: Reactome
T cell costimulation Source: Reactome
T cell receptor signaling pathway Source: GO_Central
Cellular Location
Cell membrane. Exists primarily an intracellular antigen whose surface expression is tightly regulated by restricted trafficking to the cell surface and rapid internalisation.
Involvement in disease
Systemic lupus erythematosus (SLE):
A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow.
Genetic variations in CTLA4 may influence susceptibility to Graves disease, an autoimmune disorder associated with overactivity of the thyroid gland and hyperthyroidism.
Diabetes mellitus, insulin-dependent, 12 (IDDM12):
A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
Celiac disease 3 (CELIAC3):
A multifactorial, chronic disorder of the small intestine caused by intolerance to gluten. It is characterized by immune-mediated enteropathy associated with failed intestinal absorption, and malnutrition. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes.
Autoimmune lymphoproliferative syndrome 5 (ALPS5):
An autosomal dominant primary immunodeficiency characterized by severe autoimmunity, infiltration of non-lymphoid organs, such as the intestine, lungs and brain, by hyperactive T cells and B cells, autoimmune cytopenias, and hypogammaglobulinemia in early childhood.
Topology
Extracellular: 36-161
Helical: 162-182
Cytoplasmic: 183-223
PTM
N-glycosylation is important for dimerization.
Phosphorylation at Tyr-201 prevents binding to the AP-2 adapter complex, blocks endocytosis, and leads to retention of CTLA4 on the cell surface.
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Datasheet